The serine-threonine kinase TAO3 promotes cancer invasion and tumor growth by facilitating trafficking of endosomes containing the invadopodia scaffold TKS5a

Shinji Iizuka, Manuela Quintavalle, Jose Ceja Navarro, Kyle P. Gribbin, Robert J. Ardecky, Matthew Abelman, Chen-Ting Ma, Eduard Sergienko, Fu-Yue Zeng, Ian Pass, George Thomas, Shannon McWeeney, Christian A. Hassig, Anthony B Pinkerton, Sara A Courtneidge

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Received Date: 6th February 20

Invadopodia are actin-based proteolytic membrane protrusions required for invasive behavior and tumor growth. We used our high-content screening assay to identify kinases impacting invadopodia formation. Among the top hits we selected TAO3, a STE20-like kinase of the GCK subfamily, for further analysis. TAO3 was over-expressed in many human cancers, and regulated invadopodia formation in melanoma, breast and bladder cancers. Furthermore, TAO3 catalytic activity facilitated melanoma growth in 3-dimensional matrices and in vivo. We developed potent catalytic inhibitors of TAO3 that inhibited invadopodia formation and function, and tumor cell extravasation and growth. Using these inhibitors, we determined that TAO3 activity was required for endosomal trafficking of TKS5a, an obligate invadopodia scaffold protein. A phosphoproteomics screen for TAO3 substrates revealed the dynein adaptor protein LIC2 as a relevant substrate. Knockdown of LIC2 or expression of a phosphomimetic form promoted invadopodia formation.  Thus, TAO3 is a new therapeutic target with a distinct mechanism of action.

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